title: Chronic early postnatal administration of ethylmalonic acid to rats causes behavioral deficit.
abstract: High concentrations of ethylmalonic acid (EMA) are found in tissues and biological fluids of patients affected by ethylmalonic encephalopathy (EE), as well as by deficiency of short-chain acyl-CoA dehydrogenase (SCAD) activity and other illnesses characterized by developmental delay and other neurological and muscular symptoms. The pathophysiological mechanisms responsible for the brain damage in these patients are virtually unknown. However, they may be due to the neurotoxic actions of EMA. Therefore, in the present work we investigated whether chronic exposure of EMA during early development (from 5th to 28th day of life) could alter the behavioral performance of adult rats in the Morris water maze (MWM) and elevated plus maze tasks. Control rats were treated with saline in the same volumes. We observed that adult rats pretreated with EMA presented impairment in the learning and memory in water maze task spending significantly less time in the training quadrant. However, chronic EMA administration did not affect rat performance in the elevated plus maze tasks, suggesting that anxiety-like behavior was not changed by EMA. We also evaluated the in vitro effect of EMA on lipoperoxidation and on creatine kinase (CK) activity in rat hippocampus and observed that this metabolite induced lipid peroxidation and diminished creatine kinase activity. The results provide evidence that early chronic EMA treatment induces long-lasting spatial behavioral deficit that may be possibly related to a secondary bioenergetics dysfunction and/or increase of free radical production caused by this organic acid.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Patrícia Fernanda
authors.initials: PF
authors.lastname: Schuck
authors.forename: Gustavo da Costa
authors.initials: Gda C
authors.lastname: Ferreira
authors.forename: Carolina Maso
authors.initials: CM
authors.lastname: Viegas
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Leticia Ferreira
authors.initials: LF
authors.lastname: Pettenuzzo
authors.forename: Carlos Alexandre
authors.initials: CA
authors.lastname: Netto
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008314:Malonates / Q000008:administration & dosage / Q000633:toxicity*; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013053:Spectrophotometry; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
chemical_list: D008314:Malonates; D017392:Thiobarbituric Acid Reactive Substances; C038080:ethylmalonic acid; D003402:Creatine Kinase